Effect Of Chronic Alcohol Administration Research Articles

Dissociation between diurnal cycles in locomotor activity, feeding behavior and hepatic PERIOD2 expression in chronic alcohol-fed mice

Chronic alcohol consumption contributes to fatty liver disease. Our studies revealed that the hepatic circadian clock is disturbed in alcohol-induced hepatic steatosis, and effects of chronic alcohol administration upon the clock itself may contribute to steatosis. We extended these findings to explore the effects of chronic alcohol treatment on daily feeding and locomotor activity patterns. Mice were chronically pair-fed ad libitum for 4 weeks using the Lieber-DeCarli liquid diet, with calorie-controlled liquid and standard chow diets as control groups. Locomotor activity, feeding activity, and real-time bioluminescence recording of PERIOD2::LUCIFERASE expression in tissue explants were measured. Mice on liquid control and chow diets exhibited normal profiles of locomotor activity, with a ratio of 22:78% day/night activity and a peak during early night. This pattern was dramatically altered in alcohol-fed mice, marked by a 49:51% ratio and the absence of a distinct peak. While chow-diet fed mice had a normal 24:76% ratio of feeding activity, with a peak in the early night, this pattern was dramatically altered in both liquid-diet groups: mice had a 43:57% ratio, and an absence of a distinct peak. Temporal differences were also observed between the two liquid-diet groups during late day. Cosinor analysis revealed a ∼4–h and ∼6–h shift in the alcohol-fed group feeding and locomotor activity rhythms, respectively. Analysis of hepatic PER2 expression revealed that the molecular clock in alcohol-fed and control liquid-diet mice was shifted by ∼11 h and ∼6 h, respectively. No differences were observed in suprachiasmatic nucleus explants, suggesting that changes in circadian phase in the liver were generated independently from the central clock. These results suggest that chronic alcohol consumption and a liquid diet can differentially modulate the daily rhythmicity of locomotor and feeding behaviors, aspects that might contribute to disturbances in the circadian timing system and development of hepatic steatosis.

Effect of Alcohol and Tobacco Smoke on Long-Term Memory and Cell Proliferation in the Hippocampus of Rats

Alcohol is frequently used in combination with tobacco and few studies explore interactions between these two drugs of abuse. Here, we evaluated the effect of chronic alcohol administration and concomitant exposure to tobacco smoke on long-term memory and on cell proliferation in the hippocampus of rats. Forty male Wistar rats were assigned to four groups and treated with alcohol (2g/kg by gavage) and/or exposed to tobacco smoke (from six cigarettes, by inhalation) twice a day (at 9:00 AM and 2:00 PM) for 30 days. Long-term memory was evaluated in the inhibitory avoidance test and hippocampal cell proliferation was analyzed for bromodeoxyuridine immunohistochemistry. Our results showed that alcohol, tobacco smoke, or their combination improved the long-term memory evaluated by the memory index in rats. Moreover, alcohol and tobacco coadministration decreased bromodeoxyuridine-labeled cells by 60% when compared to the control group, while alcohol treatment decreased labeled cells by 40%. The tobacco group showed a nonsignificant 26% decrease in labeled cells compared to the control group. Chronic alcohol and tobacco coadministration improves the long-term memory in rats in the inhibitory avoidance test. However, coadministration decreases the cell proliferation in the hippocampus of rats, suggesting a deleterious effect by the combined use of these drugs of abuse.

Covering the Cover

Covering the Cover

Dysregulation of myelopoiesis by chronic alcohol administration during early SIV infection of rhesus macaques.

Chronic alcohol intoxication suppresses immune function and increases osteoporosis risk suggesting bone-tissue cytotoxicity. Human immunodeficiency virus infection leads to similar impairments. This study investigated the effects of chronic alcohol administration during the early stage of simian immunodeficiency virus (SIV) infection on hematopoietic stem and progenitor cells (HSPCs) and their differentiated progeny in the bone marrow and peripheral blood of rhesus macaques. Rhesus macaques were administered alcohol or sucrose daily for a period of 3 months prior to intrarectal inoculation with 250 TCID50 of SIVmac251 . Bone marrow aspirates and blood samples were taken prior to and 2 weeks after SIV infection. Bone marrow cells (BMCs) were assessed using flow cytometric phenotyping for upstream HSPCs and for differentiated cells of the monocyte-granulocyte lineages. Likewise, cells were quantitated in peripheral blood. Of the bone marrow HSPCs, only the common lymphoid progenitor (CLP) was altered by alcohol administration pre-SIV (38 ± 9.4/10(6) BMCs vs. 226 ± 64.1/10(6) BMCs, sucrose vs. alcohol). Post-SIV, the frequency of CLPs in the bone marrow of alcohol-administered macaques decreased compared with the sucrose-administered macaques (107 ± 47.6/10(6) BMCs vs. 43 ± 16.3/10(6) BMCs). However, marrow mature cells of the monocyte lineage, specifically macrophages and osteoclast progenitors, were increased by both chronic alcohol administration and SIV infection (287% and 662%, respectively). As expected, mature cells such as granulocytes (polymorphonuclear cells), B cells, and CD4+ T cells in the peripheral blood were decreased by SIV infection (37 to 62% decline from preinfection), but not affected after 3 months of chronic alcohol administration. Chronic alcohol administration disrupts myelomonocytic development in the bone marrow during the early period of SIV infection promoting macrophage and osteoclast lineages. We predict this shift in CLP:macrophage/osteoclast balance creates an environment that favors bone resorption and immunosuppression.

The Effect of Chronic Alcohol Administration on Bone Mineral Content and Bone Strength in Male Rats

Alcohol use has been identified as a risk factor for the development of osteoporosis. Eight male Wistar rats at two months of age were alcoho-fed (7.6 g 95 % ethanol/kg b.w. per day) to evaluate the effects of long-term administration (three months) of alcohol in drinking water. We have used a dose which is considered to be comparable to a dose of 1 liter of wine or 2.5 liters of 12(°) beer used in male adults daily. The bones were tested mechanically by a three-point bending test in a Mini Bionix (MTS) testing system. The bones from alcohol-fed rats were characterized by a reduction in bone density as well as in ash, calcium and phosphate content. In alcohol-fed rats the reduction in bone mineral density (10 %) was reflected by about 12 % reduction of mechanical strength of femur (158+/-5.5 vs. 178+/-3.2 N/mm(2)). Alcohol significantly altered femoral cortical thickness. In our experiment alcohol itself did not exert any antiandrogenic effect and it did not produce changes in the weight of seminal vesicles. Liver function test (GGT, ALP, AST) did not differ between alcohol-fed rats and control rats. Alcohol-induced bone loss is associated with increased bone resorption and decreased bone formation. These results document the efficacy of alcohol at the dose of 7.6 g 95 % ethanol/kg b.w. to cause bone loss and loss of bone mechanical strength in intact rats. The results of the present study may be interpreted as supporting the hypothesis of alcohol as a risk factor for osteoporosis.

Impulsivity and response inhibition in alcohol dependence and problem gambling

IntroductionImpulsivity is a central feature of drug addiction and may arise as a result of impaired inhibitory control. The extent to which inhibitory deficits arise as a consequence of drug exposure or relate to pre-existing addiction vulnerability is unknown.Materials and methodsThis study compared measures of impulsivity in outpatients with alcohol dependence (n = 23) and problem gambling (n = 21), a putative behavioural addiction where direct effects of drug exposure may be minimal. Healthy controls (n = 27) were also tested, in a cross-sectional design. Subjects completed the stop-signal test as a neurocognitive probe of response inhibition, alongside self-report ratings of impulsivity, adult ADHD and OCD.ResultsOn the stop-signal test, Go reaction time and stop-signal reaction time were significantly slower in the alcohol-dependent group, compared with healthy controls. Healthy controls slowed their responding after successful and failed stop trials. Slowing after failed stop trials was significantly attenuated in the alcohol-dependent subjects. Go reaction time and post-error slowing were correlated with chronicity and severity, respectively, in the alcohol-dependent subjects. Problem gamblers did not differ significantly from controls on the stop-signal test, despite trait elevations in impulsivity ratings.ConclusionInhibitory control is impaired in alcohol dependence but occurs in the context of psychomotor slowing. In addition, alcohol-dependent individuals failed to show behavioral adjustment following failed stops. These deficits may represent direct effects of chronic alcohol administration on fronto-striatal circuitry.

Short‐Term Alcohol Administration Alters KiSS‐1 Gene Expression in the Reproductive Hypothalamus of Prepubertal Female Rats

Kisspeptins bind to the G-protein-coupled receptor (GPR54) to activate hypothalamic luteinizing hormone releasing hormone (LHRH) secretion at the time of puberty. Alcohol (ALC) causes depressed prepubertal LHRH release, resulting in depressed luteinizing hormone (LH) secretion and delayed puberty. Because KiSS-1 and GPR54 are important to the onset of puberty, we assessed the effects of chronic ALC administration on basal expression of these puberty-related genes within the reproductive hypothalamus, as well as hormones and transduction signaling pathways contributing to their activity. Immature female rats were fed a liquid diet containing ALC for 6 days beginning when 27 days old. Controls received either companion isocaloric liquid diet or rat chow and water. Animals were decapitated on day 33, in the late juvenile stage of development. Blood was collected for the assessment of serum hormone levels. Brain tissues containing the anteroventral periventricular (AVPV) and arcuate (ARC) nuclei were obtained for assessing expression of specific puberty-related genes and proteins. KiSS-1 mRNA levels in the AVPV and ARC nuclei were suppressed (p < 0.001) in the ALC-treated rats. GPR54 gene and protein expressions were both modestly increased (p < 0.05) in AVPV nucleus, but not in ARC nucleus. Alcohol exposure also resulted in suppressed serum levels of insulin-like growth factor-1 (IGF-1), LH, and estradiol (E(2)). As IGF-1, in the presence of E(2), can induce expression of the KiSS-1 gene, we assessed the potential for ALC to alter IGF-1 signaling in the reproductive hypothalamus. IGF-1 receptor gene and protein expressions were not altered. However, protein expression of phosphorylated Akt, a transduction signal used by IGF-1, was suppressed in the AVPV (p < 0.05) and ARC (p < 0.01) nuclei. Alcohol causes suppressed KiSS-1 gene expression in the reproductive hypothalamus; hence, contributing to this drug's ability to cause suppressed LHRH secretion and disruption of the pubertal process. We suggest that this action, at least in part, is through altered IGF-1 signaling.

Chronic cytoprotection: pentadecapeptide BPC 157, ranitidine and propranolol prevent, attenuate and reverse the gastric lesions appearance in chronic alcohol drinking rats.

Unlike severe gastric damage acutely induced by ethanol administration in rat, the ulcerogenic effect of chronic alcohol administration (3.03 g/kg b.w. or 7.28 g/kg b.w.) given in drinking water, producing liver lesions and portal hypertension, is far less investigated. Therefore, focus was on the antiulcer effect of the gastric pentadecapeptide BPC 157, GEPPPGKPADDAGLV, M.W. 1419, known to have a beneficial effect in variety of gastrointestinal lesions models (10 μg or 10 ng/kg b.w. i.p. or i.g.), ranitidine (10 mg/kg b.w. i.g.) and propranol (10 mg/kg b.w. i.g.) or saline (5 ml/kg b.w. i.p./i.g.; control). They were given once daily (1) throughout 10 days preceding alcohol consumption, (2) since beginning of alcohol drinking till the end of the study, (3) throughout the last month of alcohol consumption, 2 months after alcohol drinking had been initiated. Gastric lesions were assessed, at the end of 3 months drinking [(1), (2)] or with respect to therapeutic effect of medication before medication or at the end of therapy. Pentadecapeptide BPC 157, ranitidine and propranolol may prevent gastric lesion development if given prophylactically, before alcohol drinking. Likewise, they attenuate the lesion appearance given once daily throughout the drinking period. Importantly, when given therapeutically, they may antagonize otherwise pertinent lesion presence in stomach mucosa of the drinking rats. Thus, these results demonstrate that pentadecapeptide BPC 157, ranitidine and propranol may prevent, attenuate or reverse the gastric lesions appearance in chronically alcohol drinking rats, and may be used for further therapy, while the other studies showed that their effect (except to ranitidine) is parallel with their beneficial effect on liver lesion and portal hypertension.

Poor regression of myocardial hypertrophy following concomitant chronic alcohol ingestion and angiotensin converting enzyme (ACE) inhibition

In the following study we examined the combined effect of chronic alcohol administration and anti-hypertensive drug treatment in spontaneously hypertensive rats (SHR). SHR were fed alcohol for six weeks while taking the angiotensin converting enzyme (ACE) inhibitor lisinopril. After six weeks, protein synthesis rates, contractile protein levels and protease activities were examined in control; alcohol; control+lisinopril; alcohol+lisinopril groups. Lisinopril treatment significantly reduced left ventricular mass, protein content and contractile proteins in control rats, but these effects were not as pronounced in alcohol+lisinopril rats. Protein synthesis rates in both mixed and myofibrillar fractions were not significantly different in any of the 4 groups. The enzyme activities of the proteases cathepsin D and dipeptidyl aminopepetidase I increased in control+lisinopril rats, however, this effect was not evident in alcohol+lisinopril rats. Contractile proteins identified by one-dimensional electrophoresis showed that lisinopril treatment reduced all contractile proteins in control rats. However, in alcohol+ lisinopril rats, myosin heavy chain was higher than in control+lisinopril rats. In summary, alcohol ingestion impairs the regression of the hypertrophic myocardium in SHR on ACE-inhibitor treatment, which was reflected by altered protein metabolism. This study suggests that successful anti-hypertensive treatment may not be achieved if alcohol misuse is evident.

Liver antioxidant defenses in mice fed ethanol and the AIN-76A diet

The effects of chronic alcohol (EtOH) ingestion on antioxidant defenses in mice fed AIN-76A liquid diets were investigated. C57B1/6 female mice were divided into three groups and fed the AIN-76A liquid EtOH diet containing EtOH to provide 31% of total caloric intake (TCI), the same basic diet containing EtOH to provide 35% of TCI, or an isocaloric AIN-76A liquid control diet. After 3 weeks, the mice were killed and livers were excised for biochemical analysis. Liver reduced glutathione (GSH) levels, and activities of both Mn-Superoxide dismutase (SOD) and Cu/Zn-SOD were significantly decreased by both levels of EtOH. Activities of catalase and glutathione transferase (GT) were significantly increased, whereas glutathione peroxidase (GP) activity was not affected by either level of EtOH. Our previous study using the Lieber-DeCarli liquid EtOH diet caused a decline of total SOD and GP activities. The results suggest that chronic EtOH administration decreases liver antioxidant defenses; however, the mice fed the AIN-76A EtOH liquid diet can maintain a higher antioxidant defense capability than those fed Lieber-DeCarli EtOH liquid diet.

The effect of chronic alcohol administration on cerulein-induced pancreatitis.

Alcohol consumption i associated with pancreatitis, but the mechanism underlying this injury remains unclear. Alcohol consumption has recently been shown to increase the fragility of both rat pancreatic lysosomes and zymogen granules in vitro, which may predispose to autodigestion via the intracellular activation of digestive enzymes by lysosomal enzymes. Cerulein-induced pancreatitis is also associated with lysosomal fragility. To determine the effect of alcohol consumption on this form of pancreatic injury, the severity of pancreatitis was compared in three groups of rats following i.v. cerulein infusion: rats fed alcohol in a liquid diet, pair-fed dextrose controls, and chow-fed controls. The histological severity of pancreatitis induced by supramaximal cerulein infusion was not found to be increased by prior alcohol consumption. Since alcohol did not appear to increase the severity of pancreatic injury induced by cerulein, we sought to define biochemical parameters that might precede obvious injury. The subcellular distribution of cathepsin B activity and markers of lysosomal fragility were compared in the same groups of experimental animals. Cerulein infusion led to a marked redistribution of cathepsin B activity from the lysosomal to the zymogen-granule-enriched fractions.For animals killed in the fed state, a redistribution of cathepsin B activity toward the zymogen-granule-enriched fraction was also demonstrated in alcohol-fed animals compared to their pair-fed controls. However, chronic alcohol administration did not influence the effect of cerulein on subcellular cathepsin B distribution or lysosomal fragility. In this rat study, administration of alcohol did not increase the effects of supramaximal doses of cerulein on the pancreas.

Effects of chronic alcohol administration on lactational performance in the rat

Lactating rats, with litters adjusted to eight pups on day 2, were implanted with an atrial catheter on day 3 of lactation. Alcohol in doses of 0.0, 1.0, or 2.0 g/kg BW was infused from day 5 to 12. The blood alcohol levels (BALs) achieved following infusion of the initial doses were maintained for 4 hours daily by infusion. To control for the reduced food intake in alcohol administered groups, rats receiving alcohol doses of 0.0 and 1.0 g/kg BW were pairfed to 2.0 g/kg BW alcohol group. For infusion, combinations of 50% dextrose, 30% alcohol in saline, and saline solutions were used for 0.0 and 1.0 g/kg BW alcohol groups whereas the 2.0 g/kg BW alcohol group received 30% alcohol in saline thereby equilizing the calorie intake of the three experimental groups. On day 12, pups were separated from the dams at 0800 h, a catheter extension was attached at 0900 h and baseline blood samples for prolactin level were taken at 1000 h. Following infusion of initial alcohol doses, samples were taken for BALs. Additional samples for BALs were removed 2 h after continuing the infusion. At the end of 4-h infusion, blood samples were taken for alcohol and postinfusion prolactin levels. In groups designed to study the suckling-induced prolactin release, pups were weighed and returned to the dams. Subsequent blood samples were taken 30 min after initiation of suckling. In nonsuckled groups, blood samples were obtained at corresponding time periods. BALs were determined by head space gas chromatography and plasma prolactin by a double antibody radioimmunoassay. Suckling latency and milk consumption during the 30 min of suckling were measured. Dams' and litter weights were determined on days 2, 5, and 12 of lactation. Infusion of alcohol for 8 days from day 5 to 12 of lactation did not affect maternal body weight. However, litters nursed by dams receiving 2.0 g/kg BW alcohol weighed less on day 12 compared to all other groups. Suckling latencies did not differ among groups. Milk consumed during the 30 min of suckling was lower for the alcohol administered groups. The inhibitory effect on milk consumption was greater for the 2.0 g/kg BW group than in the 1.0 g/kg BW alcohol group. Alcohol infusion did not affect the basal prolactin, whereas, the higher dose (2.0 8/kg BW) inhibited suckling-induced prolactin release. Collectively, data from the present study demonstrate that chronic alcohol administration to lactating rats adversely affects lactation as indicated by its effect on milk yield, litter growth and suckling-induced prolactin release.

ROLE OF GABA&lt;sub&gt;A&lt;/sub&gt; RECEPTORS IN THE ACTIONS OF ALCOHOL AND IN ALCOHOLISM: RECENT ADVANCES

Brain GABAergic mechanisms are interesting with regard to their role in the actions of ethanol. The present review summarizes some of the more recent studies, most of them biochemical, electrophysiological and pharmacogenetic. While there is still a number of controversies, e.g. regarding the molecular mechanisms of ethanol enhancement of GABAA receptor-mediated anion flux and the effects of chronic alcohol administration on the receptors in experimental animals and man, there is a substantial body of evidence supporting the involvement of these mechanisms in many behavioural actions of ethanol. Two recent findings warrant further molecular biological studies on the interaction between ethanol and the GABAA receptor, and the extension of the studies to human alcoholics: first, the effects of ethanol on the GABAA receptor are dependent on a specific gamma 2 subunit with an additional phosphorylation site; second, genetically enhanced sensitivity to the motor-impairing effect of moderate ethanol doses has a likely biological basis in a single-nucleotide mutation in a cerebellum-specific GABAA receptor subunit. Further studies are also needed to establish the role of GABAergic mechanisms in alcohol misuse and addiction.

Magnesium supplementation prevents the development of alcohol-induced hypertension.

The effect of chronic alcohol administration on blood pressure was investigated in 7-week-old Wistar rats. Tail-cuff blood pressure was significantly higher in rats who received 15% ethanol in drinking water than in control rats. Intracellular free calcium concentration of lymphocytes was increased, while magnesium concentration of erythrocyte, aorta, and skeletal muscle and erythrocyte ouabain-sensitive 22Na efflux rate constant (Kos) were decreased in alcohol-induced hypertensive rats but not in control rats. Extracellular fluid volume was also increased in alcohol-administered rats. Oral magnesium supplementation (1% MgO in rat chow) attenuated the development of alcohol-induced hypertension accompanied by increased magnesium concentration of erythrocyte, aorta, skeletal muscle, and Kos and decreased intraerythrocyte sodium concentration. Norepinephrine half-life time of the heart and spleen was also increased in magnesium-supplemented rats. Blood pressure significantly correlated positively with intracellular calcium concentration and extracellular fluid volume, negatively with magnesium concentration of erythrocyte, aorta, skeletal muscle, and Kos. These results suggest that increased intracellular calcium, which was partly due to magnesium depletion and suppressed sodium pump activity, and expanded body fluid volume had a possible role in the development of alcohol-induced hypertension. It is also suggested that oral magnesium supplementation had a hypotensive effect on alcohol-induced hypertension possibly through decreased intracellular sodium concentration caused by an activation of sodium pump and decreased sympathetic nervous activity.

Adaptation of gastric mucosa to chronic alcohol administration is associated with increased mucosal expression of growth factors and their receptor.

In our previous study we found that chronic, intragastric administration of ethanol to rats produces adaptation of the gastric mucosa to subsequent challenge with an acute dose of 50% ethanol. The mechanism of this mucosal tolerance remains unexplained. Epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) stimulate cells growth and proliferation in the gastric mucosa with noted trophic effect, protect the gastric mucosa against acute injury and accelerate healing of injured mucosa. Many of these effects are exerted through EGF and TGF alpha action on their common receptor (EGFR). The aim of the present study was to determine the effect of chronic alcohol administration on cell proliferation and gastric mucosal expression and distribution of EGF, TGF alpha and EGFR. Chronic administration of ethanol (1 ml, 50% ethanol, twice daily) significantly increased the extent of gastric mucosal mucous and proliferative cell zones, the number of proliferating (DNA synthesizing) cells and mucosal expression of EGF, TGF alpha and EGFR by 13, 6, and 20-fold, respectively. Thus, adaptation of gastric mucosa to chronic alcohol administration is associated with increased cell proliferation and increased expression of mucosal EGF, TGF alpha and EGFR.

Effect of chronic alcohol administration on transketolase in the brain and the liver of rats

To estimate the nutritional and the pathological states in thiamin-deficiency-related diseases, especially Wernicke-Korsakoff syndrome, we studied the relationship among transketolase activity, transketolase concentration, and thiamin phosphate esters in rats chronically fed alcohol. In the brain of alcohol-fed rats, the enzyme activity and concentration decreased although there was no positive correlation between the two. On the contrary, transketolase activity in the liver correlated positively with concentration, and both transketolase activity and concentration were decreased in the thiamin-deficient groups. These findings suggest that transketolase in the brain may be different from that in the liver and that the alteration of the enzyme activity in the brain may be based on the conformational change of the protein molecule caused by chronic alcohol administration.

The effect of chronic alcohol administration on platelet [3H]5-hydroxytryptamine uptake and membrane lipid composition

Platelets are widely used as peripheral models for neuronal amine uptake. Their similarity with the neurosecretory activity of nerve cells, along with similar types and activities of receptors, have prompted many investigators to postulate similar pathological abnormalities in platelets during CNS disease. Ethanol and evening primrose oil (EPO) were chronically administered alone or in combination to rats in a nutritionally balanced liquid milk diet. The platelet phospholipid composition was not altered after the chronic administration of ethanol. However ethanol significantly decreased the levels of arachidonate in platelet membranes. Administration of EPO alone significantly increased the levels of linoleic acid. Platelet 5-HT uptake was measured. The affinity of these uptake sites were unaltered, while the uptake rate, V(max), was decreased by ethanol but this decrease was attenuated by the concomitant administration of EPO. The administration of EPO attenuated some of the detrimental effects due to ethanol.

Effects of chronic alcohol administration on synaptic membrane Na +[sbnd]Ca 2+ exchange activity

We have recently reported that ethanol and other n-alkanols added to in vitro assays inhibit the activity of the Na + Ca 2+ exchange system in brain synaptic plasma membrane vesicles. The present studies were undertaken to determine whether in vivo chronic ethanol administration leads to alterations in this Na + Ca 2+ antiporter that might be indicative of an adaptive response to alcohol. The Na +-dependent Ca 2+ transport activity in the plasma-membrane fractions obtained was measuredd at various Ca 2+ concentrations. Results of these experiments revealed that a 3-week ethanol regimen brought about a significant increase in the Na +-dependent Ca 2+ transport activity only in the membrane fraction enriched in synaptic junctional complexes. These membranes showed a near doubling in the maximal transport activity of the antiporter in alcohol-treated compared with the control animals. Changes in the kinetic parameters were reversible as the Na + Ca 2+ exchange activity in these membranes from animals maintained on alcohol for 3 weeks and then withdrawn for 1 week was indistringuishable from that of membranes from control animals. Thus it appears that ethanol-treated animals make a reversible adaptation in their neuronal cell membranes to compensate for the acute effects of ethanol on the Na + Ca 2+ antiporter.

Lieber-decarli alcohol diet modification to enhance growth in young rats

When male Sprague Dawley rats weighing ca 160 g were fed theLieber-DeCarli alcohol diet for 3 weeks, their growth rate was 3.8± 0.6 g/day. When the diet was supplemented with calcium phosphate (2.92 g/l), manangese carbonate (20.4 mg/l), ferric citrate (35 mg/l), zinc carbonate (9.3 mg/l), copper carbonate (1.75 mg/l), choline bitartrate (353 mg/l) and pyridoxine hydrochloride (1.2 mg/l), growth increased significantly (4.8±0.8 g/day). The daily weight gain was even greater when rats were fed the Lieber-DeCarli diet having instead of 36%, only 26% calories as alcohol (6.9±1.4 g/day). The amount of diet consumed per day also increased ca 50% as compared to the rats fed the 36% alcohol diet. Thus, the ingestion of more calories and minerals than that by rats fed the Lieber-DeCarli alcohol diet promoted a higher growth rate. Hence, supplementation of the 26% alcohol diet did not exhibit any marked effect on growth. Regardless of feeding the Lieber-DeCarli alcohol diet or its modifications, rats consumed similar amounts of alcohol (22–24 calories) per day. Our observations show that new investigations can now be carried out to examine the effect of chronic alcohol administration under conditions of improved growth in young rats.

Differential effects of chronic alcohol administration to rats on the activation of aromatic amines to mutagens in the Ames test.

Male Wistar albino rats were maintained on alcohol-containing liquid diets for 4 weeks. Hepatic post-mitochondrial preparations derived from these animals were more efficient than control in activating 4-aminobiphenyl and 2-aminofluorene to mutagens in the Ames test. The alcohol-induced enhancement in mutagenicity was not inhibited by dimethylsulphoxide indicating that the generation of hydroxyl radicals is not involved. The activation of 2-naphthylamine was not affected by the treatment with alcohol but the mutagenicities of 2-aminoanthracene, benzo[a]pyrene and 3-methylcholanthrene were inhibited. The same treatment markedly increased hepatic microsomal aniline p-hydroxylase and ethoxyresorufin O-de-ethylase activities and to a lesser extent benzphetamine N-demethylase and microsomal levels of total cytochromes P-450. It is concluded that chronic alcohol administration to rats modulates the metabolic activation of pre-carcinogens to their reactive intermediates presumably by causing the redistribution of cytochrome P-450 isozymes.